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Synthesis, structure and antimicrobial activity of substituted chalcones and their derivatives

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UDC 577.127:547.973

M.K. Ibrayev1, S.B. Akhmetova2, A.T. Takibayeva1, M.B. Issabayeva1, A.O. Nurkenov1, О.T. Seilkhanov3

1Karaganda State Technical University, Kazakhstan;

2Karaganda Medical University, Kazakhstan;

3Sh. Ualikhanov Kokshetau State University, Kazakhstan (E-mail: mkibr@mail.ru)

Synthesis, structure and antimicrobial activity of substituted chalcones and their derivatives

In the paper the interaction reactions of the hydroxyl substituted acetophenones with the substituted aromatic aldehydes in the presence of aqueous alcoholic solution of alkali (Claisen-Schmidt condensation), which is as aldol condensation were given. This reaction has a big duration and comes to the end within 62–85 h. The final product contains double bonds in α,β-position to carbonyl group. Further functionalization of the chalcones obtained was performed by their correlation with hydrazine hydrate. It was found that boiling of chalcones with hydrazine hydrate in ethanol led to an intramolecular cyclocondensation of an intermediate hydrazone to form some pyrazole derivatives. Structures of the synthesized compounds were studied with 1H and 13C-NMR spectroscopy, and data on two-dimensional (1H-1H) COSY and (1H-13C) HMQC spectra. Values of the chemical shifts, multiplicity and integral intensity of signals in one-dimensional 1H and 13C NMR spectra were determined. Homo- and heteronuclear interactions confirming structure of the compounds studied were determined with (1H-1H) COSY and (1H-13C) HMQC spectra. Data on the antimicrobial activity of the synthe- sized chalcones, pyrazolines and flavonones were showed. It was found that all studied substances practically showed a weak antibacterial activity. Exception is S. aureus culture, which possess the moderate actions for compounds of (E)-1.3-bis (2-hydroxyphenyl)-prop-2-en-1-one, (E)-1-(2-hydroxyphenyl)-3-(4-hydroxy- phenyl)-prop-2-en-1-one,(E)-3-(ethoxy-4-hydroxyphenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one and 2-(2-hy- droxyphenyl)flavone.

Keywords: substituted aromatic aldehyde, chalcone, pyrazoline, flavonone, cytokine, NF-κB transcription fac- tor.

Сhalcones are of a considerable interest caused with their easy synthesis, high pharmacological activity and possibility of application as synthon in synthesis of many biologically active heterocyclic compounds, in particular, pyrazolines and flavones. Compounds with chalcone fragment have the high antitumoral, antibac- terial, antifungal, antivirus, antimalarial, anti-hyperglycemic, anti-inflammatory and immunomodulatory ac- tivities, and demonstrate the chemoprotective and antioxidant properties [1–11]. In addition some chalcone derivatives have an ability to strengthen capillaries [5]. The traditional methods of obtaining chalcones provide the using as catalysts of such strong bases as hydroxides of alkaline and alkaline-earth metals [12]. In this connection the synthesis of new chalcones and nitrogen-containing heterocyclic compounds on their basis is represented an important object.

This paper studied the interaction reactions of the hydroxyl substituted of acetophenones with the substi- tuted aromatic aldehydes in the presence of aqueous alcoholic solution of alkali (Claisen-Schmidt condensa- tion) which was as aldol condensation. The reaction mixture was mixed with a magnetic stirrer at room tem- perature; reaction has a big duration and comes to the end within 62–85 h. The final product contains double bonds in α,β-position to carbonyl group. The chalcones obtained (1–6) are yellow or orange powders, dissol- uble in benzene and alcohol.

R R1 R4

O

R R1

CH3 O

O

C R4

H

R3 R3

+ + 40% NaOH

R2 1–6 R5

R2

R5

R = HO; R1= H; R4= CH3O; R2= R3= R5= H (1).

R = H; R1= HO; R2= HO ; R3 = R4 = R5 = H (2).

R = HO; R1 = HO; R4 = C H3O; R2= R3 = R5= H (3).

R = H; R1= HO; R2= R3 = R5 = H; R4 = HO (4).

R = H; R1= HO; R2= R5= H; R3= C2H5O; R4=HO (5).

R = Br ; R1 = H; R2 = HO ; R3 = R4 = H ; R5 = Br (6).

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The structure of the chalcones synthesized (1–6) was proved with IR- and 1H, 13C NMR spectroscopy.

IR spectrum of chalcones (1–6) demonstrates intense absorption bands at 1595–1582 cm-1 that correspond to vibrations of C=C bond attached to a carbonyl group.

1Н NMR spectrum of compound 1 in deuterated DMSO shows the high intense singlet signal with a chemical shift (3.76 ppm) and intensity of 3H belonging to protons of ОСН38 methoxy-group. Equivalent protons of methoxy- phenyl fragment of H2.6 and H3.5 were resonated with doublet signals at 6.95 (2H, 3J 8.5 Hz) and 7.77 ppm (2H, 3J 8.6 Hz), respectively. Protons at double bond of H9 and H10 give dou- blet signals at 7.74 and 7.62 ppm with intensity of 1H with splitting of 3J 17.1 and 15.3 Hz, respectively. The equivalent CH-protons of group of other aromatic system were shown with doublet signals with intensity of 2H at 6.86 (H15.17, 3J 9.2 Hz) and 8.03 ppm (H14.18, 3J 8.5 Hz).

A broadened singlet signal at 10.39 ppm demonstrated the phenolic hydroxyl in compound.

13С NMR spectrum of the studied compound 1 shows a signal of methoxy group at 55.83 ppm. Carbon atoms of the aromatic systems give signals at 114.87 (C2.6), 115.88 (C15.17), 131.05 (C3.5) and 131.57 ppm (C14.18). Signals with the chemical shifts of 161.62 (C1), 128.04 (C4), 129.84 (C13), and 162.61 (C16) ppm cor- respond to quarternary carbon atoms. Signals at 120.08 and 143.21 ppm include the carbon atoms connected by a multiple bond of C9 and C10 respectively. A weak-field signal at 187.57 ppm corresponds to C11 atom of carbonyl group.

The structure of compound (1) was confirmed by two-dimensional NMR, 1H-1H COSY and 1H-13C HMQC spectroscopy for definition of the spin-spin coupling of homo-and heteronuclear nature.

1H-1H COSY spectra of compound 1 demonstrate the spin-spin correlations through three bonds of pro- tons of aromatic systems and olefinic protons of H9 and H10. Simple correlations of protons with carbon atoms were determined by 1H-13C HMQC spectroscopy.

Reaction of cyclocondensation of hydrazines with α,β-unsaturated ketones is an important synthetic way to 1.2 azoles. Some pyrazole derivatives show properties of analgetics and inhibitors of thrombocyte aggrega- tion [13], possess the strong antibacterial [14] and anesthetized [15] actions.

In order to determine functions of the chalcones (1–6) obtained their correlation with hydrazine hydrate was studied. It was found that boiling of chalcones with hydrazine hydrate in ethanol led to an intramolecular cyclocondensation of an intermediate hydrazone to formation of pyrazole derivatives (7–11).

The structure of compounds (7–11) was confirmed by IR and NMR spectroscopy. Thus, IR spectra of py- razolines (7–11) demonstrate a strip of average intensity of C=N group of pyrazoline core at 1601–1605 cm-1.

1Н NMR spectrum of 4-(5-(4-methoxyphenyl)-4,5-dihydro-1Н-pyrazole-3-il)phenol (7) established that four groups of signals in the low field corresponded to protons of 4-hydroxy- and 4-methoxyphenyl fragments.

Two doublets at 7.40 and 7.23 ppm correspond to ortho- and meta-protons of 4- hydroxyphenyl fragment and two doublets at 6.84 and 6.72 ppm — ortho- and meta-protons of a 4-methoxyphenyl fragment. Protons of methoxy-group correspond to an intense singlet at 3.67 ppm. The following group of signals representing a triplet at 4.63–4.68 ppm is relevant to a methine proton (СНpyr) of pyrazoline fragment. Methylene protons of this fragment resonate at 2.65–2.72 ppm as two doublets. A weak signal at 9.67 ppm belongs to NH proton of a pyrazoline fragment.

R R1 R4

O

R3

+ NH2-NH2.H2O

1-6

R = HO; R1 = H; R4= CH3O; R2 = R3= R5 = H (7).

R = H; R1 = H O; R2= HO; R3= R4= R5= H (8).

R = HO; R1= HO; R4= CH3O; R2= R3= R5= H (9).

R = H; R1 = H O; R2= R3 = R5= H; R4= HO (10).

R = H; R1= H O; R2= R5= H; R3= C2H5O ; R4=HO (11).

R R1 R4

N

R3 7-11

NH

EtOH , t

R2 R2

R5 R5

1 2

3 4 5

6 8 7 9 10 11

12 13

14 15 17 16

HO OCH3

O

1

1 2 3

4 5

6

7 8 9

11 10 12

14 13 15 16

17 18 19

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Combination of the structural features of these compounds in one molecule to obtain highly effective biologically active substances is of interest in view of generality of some biogenesis processes of chalcones and flavonoids in a vegetable organism [16, 17]. In connection with this, flavonones (12–15) were obtained from synthesized 2-hydroxyl-containing chalcones under ethanol and catalytic amounts of triethylamine. Long boiling in 95 % ethanol leads to isomerization of chalcones (2–5) into flavonones (12–15). It is demonstrated that isomerization process of chalcones into flavonones in alcohol is catalyzed by water molecules.

The structure of flavonones (12–15) was proved by IR- and 1Н, 13С NMR spectroscopy. Thus, a triplet signal with a center of 1.29 ppm and multiplet at 3.98–4.03 ppm belong to protons of ethoxy-group at C20 and C19 in 1Н NMR spectrum of flavonone 15. Protons of methylene- and CH-groups of the system of condensed cores are shown in a spectrum area: H2 at 5.47, Н3 — 2.69–3.31, Н7 — 7.06, Н8 — 7.55, Н9 — 7.76 and Н10 — 7.04 ppm. Resonating at 6.77–6.90 ppm is characteristic for CH-groups of a phenyl radical. A weak pole at 9.00 ppm demonstrates a signal Н21 of hydroxyl group.

Interpretation of DEPT spectra permitted to correlate eight signals of carbon spectrum with methine groups; two signals with methylene groups and one signal with methyl group. The detailed analysis of

13С NMR of compound (15) showed that a signal at 15:29 ppm corresponded to CH3-group at C20 atom.

CH2-groups appear at 44.03 (C3) and 64.55 (C19) ppm. Eight signals of CH-groups resonate at 79.57 (С2), 113.10 (С12), 115.86 (С15), 118.57 (С7), 120.20 (С16), 121.81 (С9), 128.81 (С10) and 136.71 (С8) ppm. An additional point is that 13C NMR spectrum shows signals at 121.15, 130.18, 147.20, 147.77 and 161.76 ppm, which belong to С5, С11, С14, С13 and С6 atoms, respectively. A low field signal at 192.47 ppm belongs to a carbonyl C4 atom.

Three chalcones (2, 4, 5), two pyrazolines (8, 9) and two flavones (12, 14) were investigated to estimate their antimicrobical activity for the medicinal and sensitive museum strains of bacteria and fungi.

A microbiological laboratory to test the antibacterial and antifungal activities on the basis of Department of Microbiology at Karaganda Medical University studied the synthesized compounds on antimicrobical ac- tivity of some drugs such as (Е)-1,3-bis(2- hydroxyphenyl)-prop-2-en-1-one (2), (Е)-1-(2-hydroxyphenyl)- 3-(4-hydroxy-phenyl)-prop-2-en-1-one (4), (Е)-3-(ethoxy-4-hydroxyphenyl)-1-(2-hydroxyphenyl)prop-2-en-

R OH R3

O

R2 2-5

R = H; R1= HO ; R2= R3 = H (12).

R = HO; R1= R2= H ; R3 = CH3O (13).

R = R1 = R2= H; R3= H O (14).

R = H; R1= H; R2= C2H5O; R3= HO (15).

R

12-15 EtOH, t

O

O

R3

R2 R1

R1 R

OH R3

R2 R1 O

O H H

R

O

O

R3

R2 R1 H H

-H2O

15 O

O

OH

O-CH2-CH3

1 2 4 3 5 7 6 8 9

10

11 12 13 14 15 16

17

18 19 20 21

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1-one (5), 2,2-(4,5-dihydro-1Н-pyrazole-3,5-diil)phenol (8), 4-(5-(4-methoxyphenyl)-4,5-dihydro-1Н-pyra- zole-3-il)benzol-1,3-diol (9), 2-(2-hydroxyphenyl)flavone-4-one (12), 2-(4-hydroxyphenyl)flavone-4- one (14).

Concentrations of the tested drugs were made for an antibacterial activity, namely 1 µg and antifungal — 1 µg. Concentration of reference substances made 1 mg. The antimicrobical activity of samples was estimated on diameter of zones of a growth inhibition of test strains (mm). Diameters of zones less than 10 mm and the continuous growth in dish were estimated as lack of an antimicrobical activity, and 10–15 mm — weak activ- ity, 15–20 mm — moderate activity and over 20 mm — an expressed antimicrobical activity. Each sample was tested in three parallel studies.

The statistical processing was performed by methods of the parametrical statistics with calculation of the average arithmetic and standard errors.

Dilution was made at 1 mg of substance per 1 ml of solvent. Bacteria sensitivity to these substances was determined by a diffusive method with disks. Bacteria such as S. aureus, Bacillus subtilis, E. Coli, Ps. Aeru- giosa and Candida аlbicans were used. Antibiotic benzylpenicillin sodium salt, gentamicin and cephalosporin antibiotic of the third generation — ceftriaxone were chosen with an antibacterial activity, and an antifungal activity — nystatin.

Results of the revealed growth inhibition on some media are shown in Table.

T a b l e Antimicrobical and antifungal activities of samples.

Diameters of growth inhibition of test-strains. Solvent is 96 % ethanol No. Studied substances S. aureus B. subtilis

6633 E. coli Ps. aerugiosа

АTСС 9027 C. alblcans 1 (Е)-1,3-bis(2- hydroxyphenyl)-prop-2-en-1-

one (2)

20±1.0 18±1.0 10±1.0 10±1.0 11±1.0 2 (Е)-1-(2-hydroxyphenyl)-3-(4-hydroxy-phe-

nyl)-prop-2-en-1-one (4) 19±1.0 11±1.0 11±1.0 10±1.0 10±1.0

3 (Е)-3-(ethoxy-4-hydroxyphenyl)-1-(2-hy-

droxyphenyl)prop-2-en-1-one (5) 18±1.0 14±1.0 12±1.0 11±1.0 11±1.0 4 2,2-(4,5-dihydro-1Н-pyrazole-3,5-diil)phe-

nol (8) 14±1.0 13±1.0 13±1.0 11±1.0 12±1.0

5 4-[5-(4-methoxyphenyl)-4,5-dihydro-1Н-py- razole-3-il]benzol-1,3-diol (9)

14±1.0 11±1.0 10±1.0 10±1.0 15±1.0 6 2-(2-hydroxyphenyl)flavone-4-one (12) 18±1.0 11±1.0 10±1.0 10±1.0 11±1.0 7 2-(4-hydroxyphenyl)flavone-4-one (14) 14±1.0 13± 1.0 13±1.0 11±1.0 12±1.0

8 96 % Ethanol 9±1.0 9±1.0 9±1.0 9±1.0 9±1.0

9 Benzylpenicillin sodium salt 15±1.0 16±1.0 12±1.0

10 Gentamicin 22±1.0 30±1.0 31±1.0 30±1.0

11 Ceftriaxone 30±1.0 30±1.0 29±1.0 22±1.0

12 Nystatin 25±1.0

These cultures were seeded with a lawn method on the following media, namely egg yolk high salt agar, Endo agar, nutrient agar and Sabouraud’s medium. Then Petri dishes were incubated for a day at 37 ºC, for fungi at 28 ºC.

Thus, as a result of this research there was established that practically all studied substances showed a weak antibacterial activity. Exception is S. aureus culture for compounds of (E)-1.3-bis (2-hydroxyphenyl)- prop-2-en-1-one (2), (E)-1-(2-hydroxyphenyl)-3-(4-hydroxyphenyl)-prop-2-en-1-one (4), (E)-3-(ethoxy-4-hy- droxyphenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (5) and 2-(2-hydroxyphenyl)flavone (12) which possess the moderate actions.

Experimental

1Н and 13С NMR spectra of compounds 1–15 were recorded on JNN-ECA Jeol 400 spectrometer (fre- quency 399.78 and 100.53 MHz, respectively) in DMSO-d6 a solvent. The chemical shifts were measured concerning signals of residual protons or carbon atoms of DMSO-d6. The control of the reaction and purity of

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the compounds obtained was performed by Thin Layer Chromatography method on Silufol UV-254 plates in isopropyl alcohol-benzene-ammonia system (10:5:2). Plates were processed with iodine vapour.

General procedure of the receiving of chalcones (1–6)

The substituted acetophenone (0.013 mol) solution and aromatic aldehyde (0.013 mol) in ethanol (20 ml) were dropped to 20 ml of sodium hydroxide solution (40 %) at stirring and a room temperature. In process of aldehyde addition the reactionary mixture had yellow colour. The reactionary mixture was kept at room tem- perature for 62–95 h. Then the reactionary mixture was acidified with the diluted hydrochloric acid to neutral medium and kept for night in refrigerator (at temperature –15 ºC). The dropped out light brown powder was filtered, dried and recrystallized from benzene.

(Е)-1-(4-Hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (1). Product yield of 1 is 36 %, m.p. is 186–187 ºС. 1Н NMR spectrum, δ, ppm: 3.76 s (3Н, Н8), 6.86 d (2Н, Н15,17, 3J 9.2 Hz), 6.95 d (2Н, Н2,6,

3J 8.5 Hz), 7.62 d (1Н, Н10, 3J 15.3 Hz), 7.74 d (1Н, Н9, 3J 17.1 Hz), 7.77 d (2Н, Н3,5, 3J 8.6 Hz), 8.03 d (2Н, Н14,18, 3J 8.5 Hz), 10.39 br. s (1Н, ОН). 13С NMR spectrum, δ, ppm: 55.83 (С8), 114.87 (С2,6), 115.88 (С15,17), 120.08 (С9), 128,04 (С4), 129.84 (С13), 131.05 (С3,5), 131.57 (С14,18), 143.21(С10), 161.62 (С1), 162.61 (С16) and 187.57 (С11).

(Е)-1,3-bis(2-hydroxyphenyl)-prop-2-en-1-one (2). Product yield of 2 is 84 %, m.p. is 154–155 ºС.

1Н NMR spectrum, δ, ppm: 6.85 t (Н, Н14, 3J 8.7 Hz), 6.90–6.98 m (3Н, Н4,6,10), 7.26 t (1Н, Н15, 3J 8.2 Hz), 7.51 t (1Н, Н5, 3J 7.8 Hz), 7.81 d (1Н, Н17, 3J 9.6 Hz), 7.89 d (1Н, Н16, 3J 15.6 Hz), 8.07–8.13 m (2Н, Н3,10).

13С NMR spectrum, δ, ppm: 116.75 (С14), 118.04 (С10), 119.87 (С6), 121.03 (С4), 121.11 (С16), 121.45 (С2), 121.83 (С12), 129.55 (С17), 131.08 (С3), 132.80 (С15), 136.64 (С5), 140.95 (С11), 158.10 (С13), 194.44 (С8).

(Е)-1-(2,4-Dihydroxyphenyl)-3-(4-methoxyphenyl)-prop-2-en-1-one (3). Product yield of 3 is 23.4 %, m.p. is 175–176 ºС. 1Н NMR spectrum, δ, ppm: 3.78 s (3Н, Н20), 6.08 d (1Н, Н6, 4J 2.3 Hz), 6.26 dd (1Н, Н4ароm, 3J2.1, 8.9 Hz), 6.97 d (2Н, Н15,17, 3J 8.7 Hz), 7.69–7.77 m (2Н, Н11,12), 7.79 d (2Н, Н14,18, 3J 8.7 Hz), 8.01 d (1Н, Н3, 3J9.2 Hz). 13С NMR spectrum, δ, ppm: 55.88 (С20), 110.54 (С6), 111.51 (С4), 114.91 (С2), 114.92 (С15,17), 119.52 (С11), 128.06 (С13), 131.21 (С14,18), 133.08 (С12), 142.94 (С3), 161.73 (С16), 166.92 (С1), 167.30 (С5), 190.52 (С8).

(Е)-1-(2- hydroxyphenyl)-3-(4-hydroxyphenyl)-prop-2-en-1-one (4). Product yield of 4 is 37 %, m.p. is 155–156 ºС. 1Н NMR spectrum, δ, ppm: 6.82 d (2Н, Н13,17, 3J 8.7 Hz), 6.94 m (1Н, Н4), 6.96 d (1Н, Н11,

3J 11.9 Hz), 7.49 m (1Н, Н3), 7.69–7.75 m (2Н, Н5,6), 7.72 d (2Н, Н14,16, 3J 8.7 Hz), 8.5 d (1Н, Н10, 3J 7.8 Hz).

13С NMR spectrum, δ, ppm: 116.37 (С13), 116.67 (С17), 118.39 (С11), 119.60 (С4), 121.20 (С2), 126.17 (С12), 131.05 (С10), 131.87 (С14), 131.94 (С16), 136.53 (С3), 146.10 (С5,6), 161.12 (С15), 162.51 (С1), 194.13 (С8).

(Е)-3-(ethoxy-4-hydroxyphenyl)-1-(2-hydroxyphenyl)-prop-2-en-1-one (5). Product yield of 5 is 72 %, m.p. is 151–152 ºС. 1Н NMR spectrum, δ, ppm: 1.33 t (3Н, Н9, 3J 6.9 Hz), 4.11 k (2Н, Н8, 3J 6.9 Hz), 6.83 d (1Н, Н17, 3J 8.2 Hz), 6.93 t (1Н, Н3, 3J 8.2 Hz), 6.97 d (1Н, Н12, 3J 7.8 Hz), 7.27 dd (1Н, Н18, 3J 8.2, 1.8 Hz), 7.50 m (2Н, Н4,6), 7.75 m (2Н, Н19,20), 8.19 d (1Н, Н11, 3J 7.8 Hz). 13С NMR spectrum, δ, ppm: 15.26 (С9), 64.82 (С8), 114.11 (С4), 116.39 (С17), 118.06 (С11), 118.45 (С 3), 119.36 (С20), 121.14 (С15), 125.35 (С18), 126.16 (С5), 131.28 (С12), 136.67 (С6), 146.59 (С19), 147.77 (С1), 153.13 (С2), 162.59 (С16), 194.17 (С13).

(E)-1-(4-bromphenyl)-3-(5-brom-2-hydroxyphenyl)-prop-2-en-1-one (6). Product yield of 6 is 35 %, m.p.

is 184–185 ºС. 1Н NMR spectrum, δ, ppm: 6.84 d (1Н, Н3, 3J 9.2 Hz), 7.37 dd (1Н, Н2, 3J 8.7, 2.3 Hz), 7.73 d (2Н, Н15,17, 3J 7.4 Hz), 7.86–7.96 m (2Н, Н6,10), 8.05 d (2Н, Н14,18, 3J 8.3 Hz), 8.11 d (1Н, Н9, 3J 2.3 Hz).

13С NMR spectrum, δ, ppm: 111.40 (С1), 118.85 (С3), 121.99 (С10), 124.05 (С5), 127.85 (С16), 130.85 (С6), 132.35 (С15,17), 134.97 (С2), 137.07 (С13), 138.47 (С9), 178.78 (С11).

General procedure of the receiving of substituted pyrazolines (7–11)

0.02 mol of hydrazine hydrate was added to substituted chalcone (0.002 mol) in 10 ml of ethanol. Mixture was heated at temperature 70–80 ºС for 4 h, then cooled and diluted in 50 ml of water. A dropped out residue was filtered, washed with water and recrystallized from ethanol.

4-[5-[5-(4-Methoxyphenyl)-4,5-dihydro-1H-pyrazole-3-yl]]phenol (7). Product yield of 7 is 53 %, m.p.

is 119–120 ºС. 1Н NMR spectrum, δ, ppm: 2.68 dd (1Н, Н4ax, 2J 16.3 Hz, 3J 11.0 Hz), 3.27 dd (1Н, Н4eq,

2J 16.5 Hz, 3J 10.5 Hz), 3.67 s (1Н, Н20), 4.68 t (1Н, Н5, 3J 10.1 Hz), 6.72 d (2Н, Н8,10, 3J 8.7 Hz), 6.84 d (2Н, Н14,16, 3J 8.7 Hz), 7.21 d (2Н, Н13,17, 3J 8.7 Hz), 7.40 d (2Н, Н7,11, 3J 8.2 Hz), 9.67 br. s (1Н, ОН). 13С NMR spectrum, δ, ppm: 41.42 (С4), 55.55 (С5), 63.51 (С20), 114.22 (С14,16), 115.84 (С8,10), 124.92 (С6), 127.52 (С13,17), 128.28 (С7,11), 135.51 (С12), 149.71 (С3), 158.16 (С15), 158.86 (С9).

2,2'-(4,5-dihydro-1H-pyrazole-3,5-diil)phenol (8). Product yield of 8 is 72 %, m.p. is 124–125 ºС.

1Н NMR spectrum, δ, ppm: 2.88 dd (1Н, СН4ax, 2J 16.5 Hz, 3J 10.1 Hz), 3.53 dd (1Н, СН4eq, 2J 16.7 Hz,

3J 10.7 Hz), 5.00 t (1Н, СН5, 3J 10.5 Hz), 6.72–6.87 m (4Н, СН8,10,14,16ароm), 7.03–7.07 m (1Н, СН11ароm), 7.15–

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7.18 m (1Н, СН17ароm), 7.25 t (2Н, СН9,15ароm, 3J 7.8 Hz), 7.50 br. s (1Н, NH). NMR 13С spectrum, δ, ppm:

40.01 (С4), 57.67 (С5), 115.63 (С8), 115.91 (С14), 116.41 (С10), 117.45 (С16), 119.50 (С6,12), 127.38 (С17), 128.06 (С15), 128.54 (С9), 130.00 (С11), 153.46 (С3), 155.33 (С13), 157.28 (С7).

4-[5-(4-methoxyphenyl)-4,5-dihydro-1Н-pyrazole-3-il]benzol-1,3-diol (9). Product yield of 9 is 37 %, m.p. is 149–150оС. 1Н NMR spectrum, δ, ppm: 2.84 dd (1Н, Н4ax, 2J 11.0 Hz, 3J 11.0 Hz), 3.43 dd (1Н, Н4eq,

2J 5.3 Hz, 3J 10.5 Hz), 3.70 s (3Н, Н21),4.68 t (1Н, Н5, 3J 10.5 Hz), 6.27 m (2Н, Н8,10), 6.87 d (2Н, Н14,16,

3J 8.7 Hz), 7.05 d (1Н, Н11, 3J 8.7 Hz), 7.27 d (2Н, Н13,17, 3J 8.7 Hz), 11.22 br. s (1Н, NH). 13С NMR spectrum, δ, ppm: 41.59 (С4), 55.62 (СН3), 61.86 (С5), 102.92 (С8), 107.50 (С10), 109.44 (С6), 114.35 (С14,16), 128.39 (С13,17), 129.40 (С11), 134.76 (С12), 153.87 (С3), 159.09 (С9), 159.74 (С15), 162.10 (С7).

2-[5-[5-(4-Hydroxyphenyl)-4,5-dihydro-1H-pyrazole-5-yl]phenol (10). Product yield of 10 is 89 %, m.p.

is 110–111 ºС. 1Н NMR spectrum, δ, ppm: 2.89 dd (1Н, Н4ax, 2J 15.8 Hz, 3J 10.8 Hz), 3.47 dd (1Н, Н4eq,

2J 16.5 Hz, 3J 11.0 Hz), 4.69 t (1Н, Н5, 3J 9.8 Hz), 6.70 d (2Н, Н14,16, 3J 7.3 Hz), 6.81–6.87 m (2Н, Н8,10), 7.13–7.19 m (3Н, Н9,13,17), 7.24 d (2Н, Н11, 3J 7.3 Hz), 7.68 br. s (1Н, NH), 9.35 s (1Н, ОН19), 11.16 s (1Н, ОН18). 13С NMR spectrum, δ, ppm: 41.24 (С4), 62.36 (С5), 115.68 (С14,16), 116.23 (С8), 117.35 (С6), 119.65 (С10), 128.25 (С11), 128.37 (С13,17), 130.17 (С9), 132.79 (С12), 153.06 (С3), 157.22 (С15), 157.26 (С7).

2-Etoxy-4-[3-(2-hydroxyphenyl)-4,5-dihydro-1H-pyrazole-5-yl]phenol (11). Product yield of 11 is 93 %, m.p. is 89–90 ºC. 1H NMR spectrum, δ, ppm: 1.27 t (3Н, Н21, 3J 7.3 Hz), 2.92 dd (1Н, Н4ax, 2J 16.5 Hz,

3J 11.0 Hz), 3.49 dd (1Н, Н4eq, 2J 16.8 Hz, 3J 11.0 Hz), 3.96 q (2Н, Н20, 3J 6.7 Hz), 4.69 t (1Н, Н5, 3J 11.0 Hz), 6.69–6.74 m (2Н, Н10,14), 6.82–6.92 m (3Н, Н8,13,17), 7.16 d (1Н, Н11, 3J 7.3 Hz), 7.25 t (1Н, Н9, 3J 7.3 Hz), 7.71 s (1Н, NH), 8.87 br. s (1Н, ОН19), 11.16 s (1Н, ОН18). 13С NMR spectrum, δ, ppm: 15.32 (С21), 41.31 (С4), 62.65 (С5), 64.37 (С20), 112.75 (С17), 115.88 (С10), 116.23 (С8), 117.37 (С6), 119.65 (С13), 119.69 (С14), 128.26 (С9), 130.18 (С11), 133.29 (С12), 146.68 (С15), 147.17 (С16), 153.16 (С3), 157.26 (С7).

General procedure of the receiving of flavanones (12–15)

The reactionary mixture from 0.001 mol of substituted chalcone and catalytic amount of triethylamine in 15 ml of ethanol (95 %) was heated with backflow condenser for 8 h. The dropped out residue was filtered. It was dried at room temperature.

2-(2-hydroxyphenyl)flavone-4-one (12). Product yield of 12 is 94 %, m.p. is 147–148 ºС. 1Н NMR spec- trum, δ, ppm: 2.76 dd (1Н, Н3ax, 2J 16.7 Hz, 3J 2.7 Hz), 3.14 dd (1Н, Н3eq, 2J 17.0, Hz, 3J 13.3 Hz), 5.75 dd (1Н, Н2, 3J 13.3, 2.8 Hz), 6.77–6.83 m (3Н, Н13,14,15), 7.05 d (1Н, Н16, 3J 7.8 Hz), 6.86 d (1Н, Н7, 3J 8.2 Hz), 7.13 t (1Н, Н10, 3J 8.2 Hz), 7.49 t (1Н, Н8, 3J 7.8 Hz), 7.54 t (1Н, Н9, 3J 6.9 Hz), 8.09 s (1Н, ОН). 13С NMR spectrum, δ, ppm: 43.02 (С3), 74.85 (С2), 116.31(С13), 118.27 (С5), 118.71 (С7), 119.78 (С15), 121.64 (С8), 122.07 (С9), 125.58 (С16), 126.89 (С10), 127.34 (С14), 130.04 (С11), 136.79 (С12), 154.84 (С6), 162.03 (С4).

7-Hydroxy-2-(4-methoxyphenyl)flavone-4-on (13). Product yield of 13 is 76 %, m.p. is 146–147 ºС.

1Н NMR spectrum, δ, ppm: 2.59 dd (1Н, Н3ax, 2J 16.9 Hz, 3J 2.8 Hz), 3.08 dd (1Н, Н3eq, 2J 16.7 Hz, 3J 16.1 Hz), 3.71 s (3Н, Н20), 5.45 dd (1Н, Н2, 3J 12.8, 2.3 Hz), 6.29 s (1Н, Н7), 6.46 d (1Н, Н9, 3J 8.0 Hz), 6.97 d (2Н, Н13,15, 3J 8.2 Hz), 7.39 d (2Н, Н12,16, 3J 8.7 Hz), 8.14 d (1Н, Н10, 3J 8.7 Hz), 10.62 br. s. (1Н, ОН18). 13С NMR spectrum, δ, ppm: 43.67 (С3), 55.65 (С20), 79.25 (С2), 103.09 (С7), 111.08 (С9), 114.33 (С13,15), 114.94 (С5), 128.74 (С12,16), 131.54 (С10), 133.51 (С11), 159.85 (С14), 165.16 (С6), 166.34 (С8), 190.59 (С4).

2-(4-hydroxyphenyl)flavone-4-one (14). Product yield of 14 is 95 %, m.p. is 184–185 ºС. 1Н NMR spec- trum, δ, ppm: 2.73 dd (1Н, Н3ax, 2J 16.9 Hz, 3J 3.2 Hz), 3.18 dd (1Н, Н3eq, 2J 16.5, Hz, 3J 12.8 Hz), 5.48 dd (1Н, Н2, 3J 12.8, 2.8 Hz), 6.77 d (2Н, Н13,15,3J 8.2 Hz), 7.30 d (2Н, Н12,16, 3J 8.3 Hz), 7.00–7.05 m (2Н, Н7,9), 7.52 t (1Н, Н8, 3J 8.2 Hz, 7.75 d (1Н, Н10, 3J 7.9 Hz), 9.48 br. s (1Н, ОН18). 13С NMR spectrum, δ, ppm:

43.94 (С3), 79.40 (С2), 115.82 (С13), 115.92 (С15), 118.76 (С7,9), 121.19(С5), 128.54 (С12), 128.91 (С16), 129.69 (С11), 136.80 (С8), 158.19 (С14), 161.77 (С6), 192.40 (С4).

2-(3-etoxy-4-hydroxyphenyl)flavone-4-one (15). Product yield of 15 is 96 %, m.p. is 127–128 ºС.

1Н NMR spectrum, δ, ppm: 1.29 t (3Н, Н20, 3J 6.9 Hz), 2.71 dd (1Н, Н3ax, 2J 17.0 Hz, 3J 2.7 Hz), 3.26 dd (1Н, Н3eq, 2J 17.0 Hz, 3J 13.3 Hz), 4.00 k (2Н, Н19, 3J 6.9 Hz), 5.47 dd (1Н, СН2, 3J 12.8, 2.8 Hz), 6.78 d (1Н, Н16,

3J 8.2 Hz), 6.89 d (1Н, Н12, 3J 8.2 Hz), 7.02–7.06 m (3Н, Н7,10,15), 7.53 t (1Н, Н8, 3J 8,2 Hz), 7.76 t (1Н, Н9,

3J 7.8 Hz), 9.00 s (1Н, ОН). NMR spectrum 13С, δ, ppm: 15.29 (С20), 44.03 (С3), 64.55 (С19), 79.57 (С2), 113.10 (С12), 115.86 (С15), 118.57 (С7), 120.20 (С16), 121.15 (С5), 121.81 (Н9), 126.81 (С10), 130.18 (С11), 136.71 (С8а), 147.20 (С14), 147.77 (С13), 161.76 (С6), 192.47 (С4).

The study was performed with support of the Ministry of Education and Science of the Republic of Ka- zakhstan (project number AP05133157).

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References

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3 Tiwari K.N. In vitro inhibitory properties of ferrocene substituted chalcones and aurones on bacterial and human cell cultures / K.N. Tiwari, J.P. Monserrat, A. Arnaud Hequet, C. Ganem-Elbaz, T. Cresteil, G. Jaouen, A. Vessières, E.A. Hillard, C. Jolivalt //

Dalton Trans. — 2012. — Vol. 41. — P. 6451–6457.

4 Dao T.T. Chalcones as novel influenza A (H1N1) neuraminidase inhibitors from Glycyrrhiza inflate / T.T. Dao, P.H. Nguyen, H.S. Lee, E. Kim, J. Park, S. Lim, W.K. Oh // Bioorg. Med. Chem. Lett. — 2011. — Vol. 21, No. 1. — P. 294–298.

5 Hsieh H.K. Synthesis and anti-inflammatory effect of chalcones / H.K. Hsieh, L.T. Tsao, J.P. Wang // J. Pharm. Pharmacol. — 2000. — Vol. 52, No. 2. — P. 163–171.

6 Awasthi S.K. Potent antimalarial activity of newly synthesized substituted chalcone analogs in vitro / S.K. Awasthi, N. Mishra, B. Kumar, M. Sharma, A. Bhattacharya, L.C. Mishra, V.K. Bhasin // Med. Chem. Res. — 2009. — Vol. 18, No. 6. — P. 407–420.

7 Achanta G. A boronic chalcone derivative exhibits potent anticancer activity through inhibition of the proteasome / G. Achanta, A. Modzelewska, L. Feng, S.R. Khan, P.A. Huang // Mol. Pharmacol. — 2006. — Vol. 70. — P. 426–433.

8 Barford L. Chalcones from Chinese liquorice inhibit proliferation of T cells and production of cytokines / L. Barford, K. Kemp, M. Hansen, A. Kharazmi // Int. Immunopharmacol. — 2002. — Vol. 2. — P. 545–550.

9 Satyanarayama M. Synthesis and antihyperglycemic activity of chalcone based aryloxypropanolamines / M. Satyanarayama, P. Tiwari, K. Tripathi, A.K. Srivastava, R. Pratap // Bioorg. Med. Chem. — 2004. — Vol. 12, No. 5. — P. 883–889.

10 Hamdi N. A rapid access to new coumarinyl chalcone and substituted chromeno[4,3-c]pyrazol-4(1H)-ones and their antibac- terial and DPPH radical scavenging activities / N. Hamdi, C. Fischmeister, M.C. Puerta, P. Valerga // Med. Chem. Res. — 2011. — Vol. 20, No. 4. — P. 522–530.

11 Lahtchev K.L. Antifungal activity of chalcones: A mechanistic study using various yeast strains / K.L. Lahtchev, D.I. Batovska, S.P. Parushev, V.M. Ubiyvovk, A.A. Sibirny // Eur. J. Med. Chem. — 2008. — Vol. 43, No. 10. — P. 2220–2228.

12 Daskiewicz J.B. Organolithium mediated synthesis of prenylchalcones as potential inhibitors of chemoresistance / J.B. Daskie- wicz, G. Comte, D. Barron, A. Di Pietro, F. Thomasson // Tetrahedron Lett. — 1999. — Vol. 40, Issue 39. — P. 7095–7098.

13 Takagi K. Synthesis and reactions of some chromones / K. Takagi, M. Tanaka, Y. Murakami, H. Morita, T. Aotsuka // Eur.

J. Med. Chem. Chim. Ther. — 1986. — Vol. 21. — P. 65–69.

14 Ankhiwala M.D. Preparation and antibacterial activity of 1‐Phenyl‐3‐(2′′‐hydroxy-3′′‐bromo-4′′‐n‐butoxy-5′′‐nitrophen‐1′′‐yl)‐

5‐substituted‐phenyl‐2‐pyrazolines and 3‐(2′′‐hydroxy-3′′‐bromo-4′′‐n‐butoxy‐5′′‐nitrophen‐1′′‐yl)-5‐substituted-phenyl-2‐isoxa- zolines / M.D. Ankhiwala, H.B. Naik // Chem. Abstr. — 1991. — Vol. 4. — P. 816.

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Eur. J. Med. Chem. — 1987. — Vol. 22. — P. 239–244.

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М.К. Ибраев, С.Б. Ахметова, А.Т. Такибаева, М.Б. Исабаева, А.О. Нуркенов, О.Т. Сейлханов

Ауыстырылған халкондардың және олардың туындыларының синтезі, құрылымы және микробқа қарсы белсенділігі

Мақалада гидроксилді орынбасылған ацетофенондармен ароматты орынбасылған альдегидтердің әре- кеттесу реакцияларын, альдольді конденсацияда байқалатын сілтілі сулы-спиртті ерітіндінің (Кляйзен- Шмидт конденсациясы) қатысуымен зерттелді. Бұл реакцияның жүру ұзақтығы көп және аяқталу уа- қыты 62–85 сағ аралығын құрайды. Соңғы өнімнің құрылысында α,β-жағдайдағы карбонильді топтың қос байланысы бар. Алынған халкондардың функционализациялануы олардың гидразингидратпен әре- кеттесуі жолы арқылы жүзеге асырылды. Этанолда халкондар гидразингидратпен қайнатылған кезде аралық гидразон, молекулаішілік циклоконденсацияға ұшырап, пиразол туындылары түзілді. Синтез- делген қосылыстардың құрылысы 1Н-, 13С-ЯМР-спектроскопия және екі шекті (1Н-1Н) COSY және (1Н-

13С) HMQC-спектрлері бойынша дәлелденді. Бірөлшемді ЯМР 1Н және 13С спектрлерінде сигналдардың химиялық ығысуының, еселігінің және интегралдық қарқындылығының мәндері анықталды. Зерттел- ген қосылыстардың құрылымын дәлелдейтін гомо- және гетероядролық өзара әрекеттесулер (1H-1H) COSY және (1H-13C) HMQC спектрлері бойынша анықталды. Синтезделген халкондардың, пиразолин- дер мен флавонондардың микробқа қарсы белсенділіктерінің мәліметтері келтірілген. Барлық зерттел- ген қосылыстар бактерияға қарсы әлсіз белсенділікті көрсетті. Қалыпты айқын әсерге ие (Е)-1,3- бис(2-гидроксифенил)-проп-2-ен-1-он, (Е)-1-(2-гидроксифенил)-3-(4-гидрокси-фенил)-проп-2-ен-1-он,

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(Е)-3-(этокси-4-гидроксифенил)-1-(2-гидроксифенил)проп-2-ен-1-он, 2-(2-гидроксифенил)флавон қо- сылыстары үшін S. aureus ашытқы зеңдерінің дақылы.

Кілт сөздер: орынбасқан ароматикалық альдегид, халкон, пиразолин, флавонон, цитокин, NF-κB тран- скрипциондық факторы.

М.К. Ибраев, С.Б. Ахметова, А.Т. Такибаева, М.Б. Исабаева, А.О. Нуркенов, О.Т. Сейлханов

Синтез, структура и антимикробная активность

замещенных халконов и их производных

В статье приведены реакции взаимодействия гидроксилзамещенных ацетофенонов с замещенными аро- матическими альдегидами в присутствии водно-спиртового раствора щелочи (конденсация Кляйзена- Шмидта), которая представляет собой альдольную конденсацию. Эта реакция имеет большую продол- жительность и заканчивается в течение 62–85 ч. Конечный продукт содержит двойные связи в α,β-по- ложении к карбонильной группе. Дальнейшую функционализацию полученных халконов осуществ- ляли путем их взаимодействия с гидразингидратом. Было обнаружено, что кипячение халконов с гид- разингидратом в этаноле приводит к внутримолекулярной циклоконденсации промежуточного гидра- зона с образованием производных пиразола. Структуры синтезированных соединений изучали с помо- щью 1Н и 13С-ЯМР-спектроскопии и данных по двумерным (1Н-1Н) COSY и (1Н-13С) HMQC-спектрам.

Определены значения химических сдвигов, кратности и интегральной интенсивности сигналов в одно- мерных спектрах ЯМР 1Н и 13С. Гомо- и гетероядерные взаимодействия, подтверждающие структуру изученных соединений, определяли по спектрам (1H-1H) COSY и (1H-13C) HMQC. Приведены данные по антимикробной активности синтезированных халконов, пиразолинов и флавононов. Установлено, что практически все исследованные вещества показывают слабую антибактериальную активность. Ис- ключение составляет культура дрожжевых грибков S. aureus для соединений (Е)-1,3-бис(2-гидроксифе- нил)-проп-2-ен-1-он, (Е)-1-(2-гидроксифенил)-3-(4-гидрокси-фенил)-проп-2-ен-1-он, (Е)-3-(этокси-4- гидроксифенил)-1-(2-гидроксифенил)проп-2-ен-1-он, 2-(2-гидроксифенил)флавон, которые обладают умеренно выраженным действием.

Ключевые слова: замещенный ароматический альдегид, халкон, пиразолин, флавонон, цитокин, тран- скрипционный фактор NF-κB.

References

1 Miranda, C.L., Aponso, G.L.M., Stevens, J.F., Deinzer, M.L., & Buhler, D.R. (2000). Antioxidant and prooxidant action of prenylated and nonprenylated chalcones and flavanones in vitro. J. Agric. Food Chem., 48, 3876–3884. DOI 10.1016/S0040–

4039(99)01461–6.

2 Sivakumar, P.M., Prabhakar, P.K., & Doble, M. (2011). Synthesis, antioxidant evaluation and quantitative structure activity relationship studies of chalcones. Med. Chem. Res., 20, 482–492. DOI 10.1007/s00044–010–9342–1.

3 Tiwari, K.N., Monserrat, J.P., Arnaud Hequet, A., Ganem-Elbaz, C., Cresteil, T., Jaouen, G., Vessières, A., Hillard, E.A., &

Jolivalt, C. (2012). In vitro inhibitory properties of ferrocene substituted chalcones and aurones on bacterial and human cell cultures.

Dalton Trans., 41, 6451–6457. DOI 10.1039/C2DT12180H.

4 Dao, T.T., Nguyen, P.H., Lee, H.S., Kim, E., Park, J., Lim, S., & Oh, W.K. (2011). Chalcones as novel influenza A (H1N1) neuraminidase inhibitors from Glycyrrhiza inflate. Bioorg. Med. Chem. Lett., 21, 294–298. DOI 10.1016/j.bmcl.2010.11.016.

5 Hsieh, H.K., Tsao, L.T., & Wang, J.P. (2000). Synthesis and anti-inflammatory effect of chalcones J. Pharm. Pharmacol., 52, 163–171. DOI 10.1211/0022357001773814.

6 Awasthi, S.K., Mishra, N., Kumar, B., Sharma, M., Bhattacharya, A., Mishra, L.C., & Bhasin, V.K. (2009). Potent antimalarial activity of newly synthesized substituted chalcone analogs in vitro. Med. Chem. Res., 18, 407–420. DOI 10.1007/ s00044-008-9137-9.

7 Achanta, G., Modzelewska, A., Feng, L., Khan, S.R., & Huang, P.A. (2006). A boronic chalcone derivative exhibits potent anticancer activity through inhibition of the proteasome. Mol. Pharmacol., 70, 426–433. DOI 10.1124/mol.105.021311.

8 Barford, L., Kemp, K., Hansen, M., & Kharazmi, A. (2002). Chalcones from Chinese liquorice inhibit proliferation of T cells and production of cytokines. Int. Immunopharmacol., 2, 545–550. DOI 10.1016/ S1567–5769(01)00202–8.

9 Satyanarayama, M., Tiwari, P., Tripathi, K., Srivastava, A.K., & Pratap, R. (2004). Synthesis and antihyperglycemic activity of chalcone based aryloxypropanolamines. Bioorg. Med. Chem., 12, 883–889. DOI 10.1016/j.bmc.2003.12.026.

10 Hamdi, N., Fischmeister, C., Puerta, M.C., & Valerga, P. (2011). A rapid access to new coumarinyl chalcone and substituted chromeno[4,3-c]pyrazol-4(1H)-ones and their antibacterial and DPPH radical scavenging activities. Med. Chem. Res., 20, 522–530.

DOI 10.1007/s00044–010–9326–1.

11 Lahtchev, K.L., Batovska, D.I., Parushev, S.P., Ubiyvovk, V.M., & Sibirny, A.A. (2008). Antifungal activity of chalcones:

A mechanistic study using various yeast strains. Eur. J. Med. Chem., 43, P. 2220–2228. DOI 10.1016/ j.ejmech.2007.12.027.

12 Daskiewicz, J.B., Comte, G., Barron, D., Di Pietro, A., & Thomasson, F. (2008). Organolithium mediated synthesis of prenyl- chalcones as potential inhibitors of chemoresistance. Tetrahedron Lett., 40, 7095–7098. DOI 10.1016/S0040–4039(99)01461–6.

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13 Takagi, K., Tanaka, M., Murakami, Y., Morita, H., & Aotsuka, T. (1986). Synthesis and reactions of some chromones. Eur.

J. Med. Chem. Chim. Ther., 21, 65–69.

14 Ankhiwala, M.D., & Naik, H.B. (1991). Preparation and antibacterial activity of 1‐phenyl‐3‐(2′′‐hydroxy-3′′‐bromo-4′′‐n‐

butoxy-5′′‐nitrophen‐1′′‐yl)‐5‐substituted‐phenyl‐2‐pyrazolines and 3‐(2′′‐hydroxy-3′′‐bromo-4′′‐n‐butoxy‐5′′‐nitrophen‐1′′‐yl)-5‐sub- stituted-phenyl-2‐isoxazolines. Chem. Abstr., 4, 816. DOI: 10.1002/chin.199049179

15 Kaname, T., Masaaki, T., Hikari, M., Kuniyoshi, O., Katsuyuki, I., Naoki, N., & Masayuki, O. (1987). Synthesis and analgesic activity of 4-amino-1,2-dihydro-5-(2-hydroxyphenyl)-3H-pyrazol-3-ones and 5-amino-6-(2-hydroxyphenyl)pyrimidin-4(3H)-ones.

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